This proposal outlines experiments designed to determine the high resolution three-dimensional structure of the human histocompatibility antigen, HLA. Isomorphous crystals of two antigenic specificities HLA-A2 and HLA=A28 have been grown which are suitable for high resolution X-ray structural determination. Diffraction data have been observed to 2 A resolution. The three-dimensional structure of this polymorphic human membrane antigen would provide a framework for the rational analysis of primary sequence data from multiple allotypes. This would permit a detailed description of the sites of interaction with alloantisera and T cell receptors, as well as provide an approach to HLA-linked autoaggressive and neoplastic human diseases. Coupled with our work on the structures of the influenza virus surface antigen and proposed work on monoclonal Fab fragments, we hope to begin a detailed description of the molecular interactions in the H2 restricted cytolytic T cell response, and immunological recognition; and to provide insight into molecular and cell-cell recognition in general.